Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis is well described in invertebrates and recently documented in mammals. The prevalence and pathophysiology of mammalian apoptosis is unknown and may have clinical ramifications. The aim of this study is to investigate the apoptotic response during kidney ischemia-reperfusion (I/R) injury. Kidney I/R was initiated in anesthetized rats by occlusion of the renal pedicle for 45 min with or without pretreatment with .2 mg/kg verapamil: control animals received sham exposure. Flow was re-established after ischemia and the animals were allowed to recover for 24 h. Bilateral kidneys were harvested for DNA electrophoresis, Western analysis for p53, Northern analysis for c-myc expression, and light and electron microscopic analysis. Kidney I/R caused characteristic DNA laddering in the clamped kidney, and less extensive laddering was seen in the contralateral kidney. Light and electron microscopic analysis confirmed apoptotic morphology in the reperfused tissues. Verapamil pretreatment completely abolished DNA laddering and attenuated the microscopic evidence of apoptosis. p53 levels were increased by I/R in the ischemic kidney and moderately increased in the contralateral organ. c-myc mRNA levels were increased by the I/R insult. Kidney I/R injury may induce global apoptosis, which seems to be associated with an alteration in calcium homeostasis. The increase in p53 and c-myc mRNA levels seen with I/R may facilitate apoptosis. Calcium modulation seems to reduce apoptosis during I/R and may have therapeutic implications.
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PMID:Calcium blockade reduces renal apoptosis during ischemia reperfusion. 937 65

This study evaluates (i) constitutive levels of oncogene and p53 transcripts in chronic phase CML patients and (ii) their modulations subsequent to in vivo therapy with rIFN-alpha 2c. Peripheral blood mononuclear cells (pbmc) and bone marrow cells of 26 patients were examined for c-fos, c-myc, p53 and the hybrid bcr/abl mRNA levels. Results indicated that (i) constitutive c-fos transcript levels are significantly higher in patients subsequently responding to IFN-alpha therapy (p < 0.01) and positively correlated with the proportion of lymphocytes (r = 0.6895, p < 0.01) and negatively with the proportion of immature cells (r = -0.568, p < 0.01) contained in the pbmc preparations tested, (ii) constitutive mRNA levels of the hybrid bcr/abl, c-myc and p53 are positively correlated with each other, but failed to relate to disease parameters, and (iii) acute and chronic in vivo exposure to IFN-alpha is accompanied by upregulation of c-fos and downregulation of c-myc mRNA levels in responder patients.
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PMID:Expression of c-fos correlates with IFN-alpha responsiveness in Philadelphia chromosome positive chronic myelogenous leukemia. 938 61

We examined the incidence and association of bronchiolization of the alveoli with non-small cell lung cancer in lung resection specimens from 2 patient groups: those with non-small cell lung cancer and those diagnosed with a variety of non-neoplastic lung conditions. We observed marked variation in bronchiolization of the alveoli morphology ranging from normal to severely atypical and developed a classification scheme based on growth pattern, cell number and cytologic criteria. Patterns of differentiation, proliferation and growth factor receptor and oncogene expression were studied using immuno-histochemical and in situ hybridization techniques. While low-grade (0-I) bronchiolization of the alveoli lesions demonstrated markers similar to normal bronchiolar epithelium, a significant decrease in the Clara cell 10 kDa protein and tubulin and an increase in surfactant protein-A expression were observed in high-grade (II-III) lesions. Focal p53 expression was detected in 2 high-grade lesions, while c-myc mRNA and cJun protein were observed in all grades. No correlation was observed between bronchiolization of the alveoli incidence and histologic tumor type. A comparison of marker expression in lesions and tumors from the same case revealed a negative correlation between cytokeratin-14 and c-erbB-2 immuno-reactivity. Only one bronchialization of the alveoli lesion was found in the non-neoplastic patient group. We conclude that up to 12% of non-small cell lung cancer resection specimens contain bronchiolization of the alveoli lesions which exhibit altered morphology and patterns of differentiation.
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PMID:Bronchiolization of the alveoli in lung cancer: pathology, patterns of differentiation and oncogene expression. 946 46

Recently, 1,25-dihydroxyvitamin D3 (1,25-D3) and less hypercalcemic analogs were shown to exert a delayed cytotoxic effect on rat C6 glioma cells. 1,25-D3 induces in these cells a programmed cell death, accompanied by the induction of c-myc, p53 and gadd 45 genes. The involvement of the intracellular vitamin D receptor (VDR) remained to be determined. In this lethal process, we have investigated its role in a subclone of C6 cells, which was isolated on the basis of its resistance to 1,25-D3, and in which VDR expression was not detected either at the mRNA or protein levels. The stable transfection of a rat VDR cDNA into this clone restored its susceptibility to the cytotoxic effects of 1,25-D3. This phenomenon was accompanied by a dramatic upregulation of c-myc mRNA expression, as already described in a C6-sensitive clone. These results provide the first evidence that VDR expression, if not sufficient, is necessary to mediate 1,25-D3 cytotoxic effect in C6 glioma cells. Since VDR mRNA expression has been already reported in human brain tumors, our data imply that the identification of VDR expression could become a prerequisite in any strategy of glioma treatment with vitamin D analogs.
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PMID:Vitamin D receptor stable transfection restores the susceptibility to 1,25-dihydroxyvitamin D3 cytotoxicity in a rat glioma resistant clone. 957 11

1. The possible mechanisms of the antiproliferative and apoptotic effects of curcumin (diferuloylmethane), a polyphenol in the spice turmeric, on vascular smooth muscle cells were studied in rat aortic smooth muscle cell line (A7r5). 2. The proliferative response was determined from the uptake of [3H]-thymidine. Curcumin (10(-6)-10(-4) M) inhibited serum-stimulated [3H]-thymidine incorporation of both A7r5 cells and rabbit cultured vascular smooth muscle cells in a concentration-dependent manner. Cell viability, as determined by the trypan blue dye exclusion method, was unaffected by curcumin at the concentration range 10(-6) to 10(-5) M in A7r5 cells. However, the number of viable cells after 10(-4) M curcumin treatment was less than the basal value (2 x 10(5) cells). 3. To analyse the various stages of the cell cycle, [3H]-thymidine incorporation into DNA was determined every 3 h. After stimulation with foetal calf serum, quiescent A7r5 cells started DNA synthesis in 9 to 12 h (G1/S phase), then reached a maximum at 15 to 18 h (S phase). Curcumin (10(-6)-10(-4) M) added during either the G1/S phase or S phase significantly inhibited [3H]-thymidine incorporation. 4. Following curcumin (10(-6)-10(-4) M) treatment, cell cycle analysis utilizing flow cytometry of propidium iodide stained cells revealed a G0/G1 arrest and a reduction in the percentage of cells in S phase. Curcumin at 10(-4) M also induced cell apoptosis. It is suggested that curcumin arrested cell proliferation and induced cell apoptosis, and hence reduced the [3H]-thymidine incorporation. 5. The apoptotic effect of 10(-4) M curcumin was also demonstrated by haematoxylin-eosin staining, TdT-mediated dUTP nick end labelling (TUNEL), and DNA laddering. Curcumin (10(-4) M) induced cell shrinkage, chromatin condensation, and DNA fragmentation. 6. The membranous protein tyrosine kinase activity stimulated by serum in A7r5 cells was significantly reduced by curcumin at the concentration range 10(-5) to 10(-4) M. On the other hand, the cytosolic protein kinase C activity stimulated by phorbol ester was reduced by 10(-4) M curcumin, but unaffected by lower concentrations (10(-6)-10(-5) M). 7. The levels of c-myc, p53 and bcl-2 mRNA were analysed using a reverse transcription-polymerase chain reaction (RT-PCR) technique. The level of c-myc mRNA was significantly reduced by curcumin (10(-5)-10(-4) M) treatment. And, the level of bcl-2 mRNA was significantly reduced by 10(-4) M curcumin. However, the alteration of the p53 mRNA level by curcumin (10(-5)-10(-4) M) treatment did not achieve significance. The effects of curcumin on the levels of c-myc and bcl-2 mRNA were then confirmed by Northern blotting. 8. Our results demonstrate that curcumin inhibited cell proliferation, arrested the cell cycle progression and induced cell apoptosis in vascular smooth muscle cells. Curcumin may be useful as a template for the development of drugs to prevent the pathological changes of atherosclerosis and post-angioplasty restenosis. Our results suggest that the antiproliferative effect of curcumin may partly be mediated through inhibition of protein tyrosine kinase activity and c-myc mRNA expression. And, the apoptotic effect may partly be mediated through inhibition of protein tyrosine kinase activity, protein kinase C activity, c-myc mRNA expression and bcl-2 mRNA expression.
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PMID:Effect of curcumin on cell cycle progression and apoptosis in vascular smooth muscle cells. 972 Jul 70

During the course of a study aimed at improving antisense oligodeoxynucleotide-mediated ex vivo bone marrow purging of patients suffering from chronic myeloid leukemia (CML), the properties of a number of antisense structures intended to reduce the expression of c-myc, mutant p53, and bcr-abl mRNAs and proteins were examined. The majority of the antisense oligodeoxynucleotides were designed to be capable of directing ribonuclease H (RNase H) cleavage of their target mRNAs. Streptolysin O (SLO) reversible permeabilization was used to deliver the oligodeoxynucleotides into the CML line KYO-1. We found that the efficiency and specificity of antisense oligonucleotide-induced reductions of target protein expression depended on target protein half-life, the oligonucleotide structure, and the specific sequence within the target mRNA. Transient reductions of c-myc mRNA and protein were achieved with a chimeric methylphosphonate-phosphodiester oligodeoxynucleotide antisense to the initiation codon, but cell proliferation was unaffected. In contrast, a chimeric oligodeoxynucleotide of similar structure targeted to an alternative site in the coding region of c-myc mRNA reduced target mRNA and protein levels for over 24 hours and halted cell proliferation. Chimeric methylphosphonate-phosphodiester oligodeoxynucleotide antisense to a point mutation in KYO-1 p53 mRNA efficiently reduced target mRNA expression, but only small, transient reductions in p53 protein expression were observed. However, a chimeric methylphosphonate-phosphorothioate oligodeoxynucleotide targeted to the same site reduced p53 protein to 30% of control levels over a 48-hour period. BCR-ABL protein expression was unaffected by chimeric oligodeoxynucleotides targeted to the breakpoint in bcr-abl mRNA, even when mRNA levels at early times were substantially reduced.
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PMID:The influence of target protein half-life on the effectiveness of antisense oligonucleotide analog-mediated biologic responses. 974 66

The survival of 119 colorectal cancer patients was analyzed in the light of the overexpression status of the c-myc proto-oncogene mRNA and the point mutation status of the p53 tumor suppressor gene in the primary adenocarcinoma. The presence of >3 fold overexpression of c-myc mRNA in the primary tumor was found to be associated with a better prognosis than patients who evinced no overexpression (P = 0.02, log rank analysis). Point mutation of the p53 tumor suppressor gene was found to be associated with a poorer patient prognosis (P = 0.007, log rank analysis). Endogenous levels of c-myc and point mutation of p53 both contributed independently toward a poorer patient prognosis in Cox regression modeling. The better prognosis seen in patients who overexpress c-myc was offset when c-myc overexpression was coupled with a point mutated p53 gene. These results suggest that in colorectal adenocarcinoma c-myc deregulation leads to increased apoptotic death, but that this response may be modulated by a more downstream event such as point mutation of the p53 gene.
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PMID:Overexpression of the c-myc proto-oncogene in colorectal carcinoma is associated with a reduced mortality that is abrogated by point mutation of the p53 tumor suppressor gene. 981 66

Apoptosis plays a major role in gastrointestinal epithelial cell turnover, ulcerogenesis and tumorigenesis. We have examined apoptosis induction by non-steroidal anti-inflammatory drugs (NSAIDs) in human gastric (AGS) cancer cells and the role of protein kinase C (PKC) and apoptosis-related oncogenes. After treatment with aspirin or indomethacin, cell growth was quantified by MTT assay, and apoptosis was determined by acridine orange staining, DNA fragmentation and flow cytometry. The mRNA and protein of p53, p21waf1/cip1 and c-myc was detected by Northern and Western blotting respectively. The influence of PKC on indomethacin-induced apoptosis was determined by co-incubation of 12-O-tetradecanoylphorbol 13-acetate (TPA). The role of c-myc was determined using its antisense oligonucleotides. The results showed that both aspirin and indomethacin inhibited cell growth and induced apoptosis of AGS cells in a dose- and time-dependent manner, without altering the cell cycle. Indomethacin increased c-myc mRNA and protein, whereas p53 and p21wafl/cip1 were unchanged. Down-regulation of c-myc by its antisense oligonucleotides reduced apoptosis induction by indomethacin. TPA could inhibit indomethacin-induced apoptosis and accumulate cells in G2/M. Overexpression of c-myc was inhibited by TPA and p21waf1/cip1 mRNA increased. In conclusion, NSAIDs induce apoptosis in gastric cancer cells which may be mediated by up-regulation of c-myc proto-oncogene. PKC activation can abrogate the effects of NSAIDs by decreasing c-myc expression.
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PMID:Non-steroidal anti-inflammatory drug-induced apoptosis in gastric cancer cells is blocked by protein kinase C activation through inhibition of c-myc. 1002 4

Human head and neck squamous cell carcinoma (HNSCC) lines infected with a replication-defective Ad5CMV-p53 vector bearing a wild-type human p53 gene were used to examine alterations in the production of proteins implicated in regulating apoptosis. Because HNSCC lines express abundant levels of c-myc, and simultaneous expression of c-myc and p53 is known to trigger apoptosis in other cells, cooperation between these two genes was examined. Surprisingly, levels of c-myc mRNA and protein were rapidly and profoundly suppressed after infection with wild-type p53. Suppression of c-myc using antisense oligodeoxynucleotides (in the absence of p53) was sufficient to trigger apoptosis in Tu-138 cells, raising the possibility that the reduction of c-myc may be involved in at least one of the cell death pathways mediated by p53. Expression of a panel of Bcl-2 homology proteins was also examined in HNSCC lines undergoing p53-mediated apoptosis. No changes in Bcl-2, Bak, or Bcl-xS were found after p53 expression. Increased levels of the apoptosis-accelerating protein Bax were found in HNSCC lines after infection with Ad5CMV-p53. Induction of the apoptosis-inhibiting protein Bcl-xL was observed in Tu-167 cells and may account for the delayed onset of apoptosis in these cells. These studies suggest that multiple pathways may regulate apoptosis after transient overexpression of p53.
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PMID:Expression of apoptosis-related genes in human head and neck squamous cell carcinomas undergoing p53-mediated programmed cell death. 1003 86

Nonsteroidal anti-inflammatory drug (NSAID)-induced apoptosis is considered to be an important mechanism in the antineoplastic effects and damage produced by the drugs in the gastrointestinal tract. In this study, two different gastric cancer cell lines, MKN28 (mutant-type p53) and AGS (wild-type p53), were compared as to growth inhibition, apoptosis, and cell cycle and apoptosis-related gene expression in response to indomethacin treatment. Cell growth was measured by MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Apoptosis was characterized by acridine orange staining and DNA fragmentation, and cell cycle kinetics by flow cytometry. The mRNA and protein levels of p53, p21waf1/cip1, and c-myc were determined by Northern and Western blotting. The results showed that indomethacin initiated growth inhibition and apoptosis in both cell lines without cell cycle shifting. AGS cells were more sensitive to growth inhibitory activity and apoptosis of indomethacin than MKN28 cells. In MKN28 cells, the levels of p53, p21waf1/cip1, and c-myc mRNA remained unchanged over the 24-hr treatment with indomethacin, but the p53 protein level was elevated after 4 hr. There was no change in the p21waf1/cip1 and c-myc protein levels in the MKN28 cells. In AGS cells, a progressive increase in c-myc mRNA and protein levels was noted, while p53 and p21waf1/cip1 remained unchanged. It can be concluded that wild-type p53 and/or up-regulation of c-myc is associated with indomethacin-mediated differential apoptosis in gastric epithelial cells.
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PMID:Differential apoptosis by indomethacin in gastric epithelial cells through the constitutive expression of wild-type p53 and/or up-regulation of c-myc. 1040 34


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